The invention relates to a method of inhibiting bone resorption, halting or retarding loss of bone mass, reducing fractures, improving bone repair and preventing or treating osteoporosis, particularly in post-menopausal women. Treatment of additional diseases/disorders is also disclosed.
The current major bone diseases of public concern include osteoporosis (post-menopausal, idiopathic and secondary to immobilization or drugs such as glucocorticoids), bone lesions due to metastases, hypercalcemia of malignancy, oral bone loss due to periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation. This process of bone remodeling or bone turnover continues throughout life and replaces about 14% of the skeletal mass per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12-20% mortality rate within the first two years, while over 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
There is evidence in the literature that prostaglandins act as modulators of the bone resorption process. There is also evidence that certain non-steroidal anti-inflammatory agents (NSAID's) may (to some degree) reduce bone resorption. See, for example, the reports on the use of Diclofenac sodium by post menopausal women (Am. J. Medicine, Vol. 96, pp. 349-353, 1994); naproxen (J. Bone Mineral Res., Vol. 5, pp. 1029-1035, 1990) in laboratory animal models.
As is appreciated by those of skill in the art, the natural processes of bone resorption and bone renewal are in constant dynamic equilibrium. This equilibrium, however, may differ with time (age), sex, and/or hormonal balance. Accordingly, the existence of evidence supporting the premise that the administration of an NSAID to post-menopausal women, may (to some degree) retard bone resorption, can not betaken as an indicator that the administration of NSAID's will affect a sufficient shift in equilibrium to halt or retard loss of bone mass, reduce fractures, improve bone repair or provide an effective means of preventing or treating osteoporosis. See in contrast GB 2,118,042 issued Jan. 15, 1986 (U.S. Pat. No. 4,621,077), which discloses the use of bisphosphonates, including alendronate, which have been shown effective in the prevention of bone loss in post-menopausal women.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase has been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, evidence is mounting that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, the inducible form, cyclooxygenase-2, appears to be mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines.
Surprisingly, the applicant has now found that selective cyclooxygenase-2 inhibitors, and in particular the compounds of formula I as described below are effective in inhibiting bone resorption, halting or retarding loss of bone mass, reducing fractures, improving bone repair and preventing or treating osteoporosis.